Type 2 diabetes is a particularly debilitating disease and is endemic for a large proportion of the world's population. The unmet challenges in disease management are the lack of long-term efficacy in reducing hyperglycemia and the inability to stop progression. Glucagon-like peptide-1 (GLP-1), a natural gut hormone, provides a platform for therapeutics to combat the disease. Peptides in general have potent and selective biological activities, making them highly desirable as therapeutics, but a major obstacle to more widespread use in medicine is limited proteolytic stability. The high potency of GLP-1 itself is nullified by a half-life of less than 2 min after injection. Our laboratory has been developing GLP 1 analogs with enhanced proteolytic stability for several years: we have now discovered that a simple N-terminal modification, designed to deliver large stability enhancements, preserves binding and activity of GLP-1 in cell- based assays. Historically, gains in stability via chemical modification of the N-terminal peptide sequence have been obtained only at the expense of potency, so that frequent injections would still be needed to maintain therapeutic benefit. Our research program at Tufts has experience in the study of G Protein-Coupled Receptors (GPCRs) and has produced notable innovations in the design and synthesis of peptide ligands that modulate such receptors. The goal of this proposal is to prove that strong binding at the GLP-1 receptor (GLP-1R), full agonist activity, and protease stability can be demonstrated for our N-terminal modified peptides, without otherwise altering the N- terminal sequences. If successful this would be a completely novel approach to peptide stabilization. Taken together, these studies will set a benchmark and provide a blueprint for the modification of other peptides that suffer from poor protease stability. At the end of the period of support by the STTR mechanism, these studies should set the stage for this platform technology to be implemented for other peptides that can be stabilized in a similar fashion.